CN1021050C - Preparing method for butyrumid derivative - Google Patents

Preparing method for butyrumid derivative Download PDF

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CN1021050C
CN1021050C CN87105515A CN87105515A CN1021050C CN 1021050 C CN1021050 C CN 1021050C CN 87105515 A CN87105515 A CN 87105515A CN 87105515 A CN87105515 A CN 87105515A CN 1021050 C CN1021050 C CN 1021050C
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CN87105515A (en
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彼得·撒迪厄斯·加拉格尔
特伦斯·艾伦·希克斯
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/42—One nitrogen atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

The present invention relates to compounds of the following formula have pharmaceutical properties, and salts thereof, and processes for their preparation.

Description

Preparing method for butyrumid derivative
The present invention relates to new compound and pharmaceutical use thereof.
Some phenyl crotonamide compounds with medicinal property are open in English Patent 1571990.This compound can be replaced arbitrarily by various substituting groups on phenyl ring, and substituting group comprises methyl or ethyl.
By contrast, The compounds of this invention is the Hete rocyclic derivatives that replaces.They have following logical formula I and salt thereof:
Figure 871055155_IMG10
（Ⅰ）
In the formula, X is R 1(HO) C=C(CN)-, R 1(CO)-CH(CN)-or
R 1And R 2Respectively be hydrogen or C 1-6Alkyl, R 3, R 4, R 5And R 6Respectively be hydrogen, hydroxyl, halogen, nitro, cyano group, carboxyl, C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4The C that alkylthio, halogen replace 1-4The C that alkyl, halogen replace 1-4The C that alkoxyl group, halogen replace 1-4Alkylthio, C 2-5Phenoxy group, the R ' R " N-, wherein R ' and R " of alkoxy carbonyl, the phenyl that replaces arbitrarily, fetch bit arbitrarily respectively are hydrogen or C 1-4Alkyl, or R " ' CONH-, wherein R " ' be C 1-4Alkyl, or formula-CR 7R 8R 9Group, R wherein 7, R 8And R 9Respectively be C 1-6The C that alkyl, halogen replace 1-6Alkyl or the phenyl that replaces arbitrarily, or R 7And R 8Link together with carbon atom and combine with it, form the cycloalkyl that contains 3-7 carbon atom, or R 7, R 8And R 9With carbon atom and combination with it, form the bicyclic alkyl that contains 4-9 carbon atom, and Y is 5 or 6 yuan a heterocycle except that pyrazoles.
The compounds of this invention and pharmaceutically acceptable salt thereof in the possibility test of treatment immunological disease such as sacroiliitis and treatment and the sick diseases associated of leukotrienes, prove that it is effective medicine.
Obviously, with X be R 1(HO) compound of-above-mentioned formula I C=C(CN) can exist with tautomerism shape, is shown by following column balancing:
Figure 871055155_IMG12
When adopting common synthetic method to prepare, compound is the Z of above-listed formula II and (III) and the mixture of E isomer, and the Z type is preponderated.The Z type can separate with conventional crystallization method with the E type.The ketone type is the intermediate of synthesising different structure body (II) and (III).
In the formula I, C 1-6Alkyl can be with side chain, also can not be with side chain, and can be methyl, ethyl, propyl group, 1-first and second bases, butyl, 1-first propyl group, 1,1-diformazan ethyl, amyl group or hexyl.Equally, C 1-4Alkyl can be methyl, ethyl, propyl group or 1-first and second bases, and C 1-4Alkoxyl group and C alkylthio then are respectively from deriving by Sauerstoffatom or sulphur atom and the group that phenyl ring is connected.When these groups are replaced by halogen, replace one or more hydrogen atoms by halogen atom, halogen atom is that fluorine, chlorine or bromine are good, especially with fluorine or chlorine atom the best.The preferred examples of halogen-substituted alkyl is a trifluoromethyl substituent.R 3, R 4, R 5And R 6Can be halogen also, preferably fluorine, chlorine or bromine when being halogen.Work as R 3, R 4, R 5Or R 6Be C 2-5During carbalkoxy, then be the C of formula ROCO- 2-5Carbalkoxy, wherein R is C 1-4Alkyl is worked as R 3, R 4, R 5Or R 6For substituted-phenyl arbitrarily or arbitrarily during substituent phenoxy, then preferably 1-3 group replaces arbitrarily phenyl in the following groups by being selected from, and these groups are exactly: halogen, nitro, cyano group, carboxyl, C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4The C that alkylthio, halogen replace 1-4The C that alkyl, halogen replace 1-4The C that alkoxyl group, halogen replace 1-4Alkylthio and C 2-5Carbalkoxy.
Work as R 7And R 8When constituting cycloalkyl, cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl, works as R 7, R 8And R 9When constituting bicyclic group together, then should preferably contain 4-7 carbon atom by base, dicyclo (4.1.0) heptyl promptly is an example wherein.
Heterocyclic radical Y can be the heterocycle of any 5 yuan or 6 yuan except that pyrazoles, and its example comprises the group by thiophene, furans, pyrroles, pyridine, thiazole, isothiazole, oxazole, isoxazole, imidazoles and pyrimidine derivates.The tie point of phenyl and alpha-cyano beta-keto acyl amino can be any available carbon atom on heterocycle.The preferred person of Y is following disubstituted:
2, the 5-thiophene
2, the 4-thiophene
2, the 5-furans
2,5-pyrroles
2, the 6-pyridine
2, the 5-thiazole
2, the 5-oxazole
2, the 5-imidazoles
3,5-isothiazole and
2, the 6-pyrimidine.
If desired, heterocyclic radical can be substituted, for example can be by one or more C 1-4Alkyl replaces, such as by 1 or 2 C 1-4Alkyl is methyl substituted especially.Particularly nitrogen-atoms can be by alkylation on the pyrrole ring.
Certainly, owing to the existence of acid hydroxy group, also might prepare the salt of The compounds of this invention.This class salt comprises in the present invention.They can be any known base addition salt, the example of this class salt is by those salt of deutero-in ammonium hydroxide and basic metal, alkaline earth metal hydroxides, carbonate and the supercarbonate, and by aliphatic amine and aromatic amine, aliphatic diamine and hydroxyalkyl amine deutero-salt.The alkali that is particularly useful for making a following class salt comprises ammonium hydroxide, salt of wormwood, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, quadrol, hexahydroaniline and thanomin.Be the best with sylvite and sodium salt especially wherein.In addition, all right tangible salifiable other groups can provide base addition salt and acid salt on phenyl ring.With pharmaceutically acceptable salt is the best, but other salt is also contained in the present invention, because they can be used for preparing other compounds or obtain good crystal formation.
The preferred compounds of formula I is exactly following these compounds:
(ⅰ) X is R 1(HO) C=C(CN)-, more precisely
Figure 871055155_IMG13
(ⅱ) R 3, R 4And R 5Be hydrogen
(ⅲ) R 2Be hydrogen
(ⅳ) R 2It is methyl
(ⅴ) R 1Be C 1-6Alkyl, the best is a methyl
(ⅵ) R 6Be hydrogen, C 1-4Alkyl, the C that halogen replaces 1-4Alkyl or-CR 7R 8R 9, R wherein 7, R 8, R 9Respectively be C 1-4Alkyl
(ⅶ) R 6Be-CR 7R 8R 9, R 7, R 8And R 9Respectively be C 1-4Alkyl
(ⅷ) R 7And R 8The common cycloalkyl that constitutes 3-7 carbon atom, R 9Be C 1-6Alkyl or phenyl
(ⅸ)-CR 7R 8R 9Group and phenyl ring link position are the contraposition positions with respect to amido.
One group of compound and salt thereof that preferable compound is a following formula
In the formula, R 1Be C 1-4Alkyl, R 2Be hydrogen or methyl, R 7, R 8And R 9Respectively be hydrogen or C 1-4Alkyl, Y is thiophene preferably.
Another group preferred compounds is the compound and the salt thereof of following formula
Figure 871055155_IMG15
In the formula, R 1Be C 1-4Alkyl, R 2Be hydrogen or methyl, R 7And R 8The common cycloalkyl that constitutes 3-7 carbon atom, R 9Be C 1-4Alkyl or phenyl, Y is thiophene preferably.
The present invention also comprises the method for producing the formula I compound, comprising:
A. formula IV compound and formula (V) compound reaction
In the formula, M is an alkali valence metal ion, R 1And R 3To R 8Definition the same, the salt of Sheng Chenging can be arbitrarily and acid-respons thus, discharging X is R 1(HO)-free hydroxy compound C=C(CN),
B. formula VI compound and alkali reaction
Figure 871055155_IMG17
（Ⅵ）
In the formula, R 1To R 8Definition the same, the salt of Sheng Chenging can be arbitrarily and acid-respons thus, discharging X is R 1(HO)-free hydroxy compound C=C(CN),
C. the amine of formula (VII) compound and formula (VIII) reaction
In the formula, Z is the fontanel element, chlorine preferably, and X is in the compound that obtains
Figure 871055155_IMG19
Or
D. hydrolyzing type (IX) compound
Figure 871055155_IMG20
（Ⅸ）
In the formula, R 1To R 6Definition the same, R 10It is leavings group.
Above-mentioned reaction a. preferably carries out in such as tetrahydrofuran (THF) one class inert organic solvents and under-30 ℃ of-100 ℃ of temperature condition, obtains the salt of following formula
Figure 871055155_IMG21
By the effect of aqueous inorganic acids such as all example hydrochloric acids one class acid and under 0 ℃ of-100 ℃ of temperature condition, be converted into the free hydroxy compound shown in the formula I.This is that synthetic Y is the best route of the formula I compound of thiophene or furans.
Preparation formula IV compound can pass through the effect such as the alkali of ethanolic soln one class of alkali metal alcoholates, opens the ring of the suitable Isoxazole derivative of following formula,
Figure 871055155_IMG22
Under 5 ℃ of-80 ℃ of temperature condition, obtain the compound that M is an alkalimetal ion, or under-80 ℃ of-30 ℃ of temperature condition, react, obtain the compound that M is a lithium by the tetrahydrofuran solution of 5-methyl-isoxazole and butyllithium, that continues reacts with alkyl bromide that is fit to or alkyl iodide arbitrarily, obtains R 1Be C 2-6The formula IV reactant of alkyl.Synthesis type (V) compound can adopt ordinary method, for example reacts at dimethyl formamide solution by the carboxylic acid derivative that is fit to and diphenyl phosphoryl azide and triethylamine, and the trinitride that obtains thus of reflux.
About reaction b, be preferably under-80 ℃ of-100 ℃ of temperature condition, be preferably in such as carrying out in tetrahydrofuran (THF), ethanol or the methyl-sulphoxide one class inert organic solvents.
The preparation of formula VI reactant is easy to, and (the suitable amine condensation of VII) De isoxazolyl fontanelle compound and formula (VIII) can obtain through type
Figure 871055155_IMG23
In the formula, Z is the fontanel element, and the best is a chlorine.
Reaction is preferably under-70 ℃ of-110 ℃ of temperature condition, carries out in toluene one class inert organic solvents.
Formula (VII) compound can be by following reaction sequence preparation
Figure 871055155_IMG24
Formula (VIII) compound can adopt ordinary method preparation, for example under the formula I compound condition of Y Wei oxazole, and method (J.Org.Chem.1981,46, the 2069) preparation that can adopt van Leusen etc. to be introduced.
R 2Be C 1-6The formula of alkyl (VIII) compound can from corresponding amine preparation, for example be handled with the malonaldehydic acid acid anhydride earlier by the alkylation that is fit to, and that continues uses lithium aluminium hydride reduction, obtains the compound that R is a methyl; Or earlier with suitable alkane etheride acidylate, that continues uses lithium aluminium hydride reduction, obtains the compound that R is the C alkyl.In addition, this compound also the diethyl ether solution reduction corresponding isocyanate of available lithium aluminum hydride be prepared.
About above-mentioned reaction d, be preferably under 5 ℃ of-100 ℃ of conditions and in water medium, carry out.Can use mineral acid example hydrochloric acid or alkali metal base such as sodium hydroxide.R 10Be removed leavings group in hydrolysis reaction, C exactly says so 1-4Alkoxyl group, each C naturally of phenoxy group or R ' R " N-, wherein R ' R " 1-4Alkyl.
The preparation of formula (IX) compound can from the suitable amine of following formula earlier with cyanoacetic acid or cyanoacetate reaction, carry out that dewatering agent is used in this reaction such as dicyclohexylcarbodiimide is dissolved in suitable solvent such as methylene dichloride is handled, or by heating,
Figure 871055155_IMG25
Obtain the compound of following formula, this compound preferably uses the zinc chloride one class Lewis acid of catalytic amount to react reacting with ortho-acetic acid trialkyl ester or higher alkane acid esters in diacetyl oxide then,
Figure 871055155_IMG26
Obtain required intermediate.
Obviously, the substituting group of each on phenyl ring shown in the formula I can exchange.For example after main step of condensation was finished, carboxyl substituent on the ring or the carboxyl that is connected with the last phenyl substituent of ring can be produced by hydrolysis suitable nitrile or carbalkoxy derivative.
By test, prove that The compounds of this invention can improve immunne response, test certainly these compounds inhibition T proliferation of cells of bringing out by concanavalin A and graft to host's reaction, the i.e. mediation process of T cell.The compounds of this invention also has curative effect in the adjuvant arthritis test, (B.B.Newbould Chemotherapy of Arthritis Induced in Rats by Mycobacterial Adjuvant, Br.J.Pharmacol.21,127-136(1963)).
Above-mentioned feature description The compounds of this invention has the anti-inflammatory feature, and can be used for treating for example sacroiliitis, can also treat immune disorders, as general lupus and transplant rejection.
The compounds of this invention can also suppress the formation of 5-lipoxygenase product, (the J.Pharmacologieal Methods 9 that in its test, is introduced as J.Harvey and D.J.Osborne, 147-155(1983)), the illness that can be used for treating relevant leukotrienes also is described thus.These illnesss comprise the anaphylaxis of immediate hypersensitivity, pulmonary system, for example aspect pulmonary dysfunction as extrinsic asthma and industrial asthma, aspect other inflammatory disorder relevant with acute infection or chronic infection disease, as allergic dermatosis, atopic eczema and atopic eczema, psoriasis, contact hypersensitivity, vasodilation, bronchitis, gallbladder cystic fibrosis, and rheumatic fever.In addition, because The compounds of this invention can suppress the formation of leukotrienes, thus various inflammation are all had the curative effect of possibility, and can be used for the treatment of cancer.
The compounds of this invention is dispenser in every way, for example oral or rectal administration, and inhalation dosing, local dispenser or parenteral dispenser are for example with the pharmaceutical compositions drug administration by injection.This based composition is an integral part of the present invention, and with currently known methods preparation in the pharmaceutical technology field, comprises at least that usually a kind of active compound and pharmaceutically acceptable diluent or carrier are combined.When making the present composition, usually activeconstituents is mixed with carrier, or dilute, and/or to use carrier package, the form of carrier can be capsule, sachet, paper or other packing materials with carrier.Carrier can be used as thinner, can be solid, semisolid or the liquid substance that is used as carrier, vehicle and the medium of activeconstituents.The form of composition can be a solid or in liquid medium, tablet, lozenge, sachet, cachet, elixir, suspension agent, aerosol are arranged, the ointment that contains (weight) below 10% active compound, soft gelatin capsule and hard gelatin capsule, suppository, injection solution and suspension, and the pulvis of sterile packed.The specific form of inhaled medication comprises the use aerosolizer, atomizer and vaporizer.
Some examples that are fit to carrier are: lactose, glucose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch, Sudan Gum-arabic, calcium phosphate, alginate, tragakanta, gelatin, syrup, methylcellulose gum, methyl hydroxybenzoate, nipasol, talcum powder, Magnesium Stearate and mineral oil.The present composition can be mixed with activeconstituents energy quick-release and slow release type preparation after patient's medication by this technical field known technology.
Be mixed with the composition of unit dosage form, preferably per unit dosage contains 5 milligrams to 500 milligrams, and commonly used is 25 to 200 milligrams of activeconstituentss.Individual on " unit dosage form " family of languages finger-type body is applicable to that the unitary dose of patient and animal, per unit contain the active substance of the predetermined amount that the required curative effect of with good grounds generation calculates, and with desired pharmaceutical carrier combination.
In wide dosage range, The compounds of this invention all is that effectively for example the adult per daily dose scope of general therapeutic is 0.5-300 milligram/kilogram, and scope commonly used then is 5-100 milligram/kilogram.But self-evident, in fact the consumption of compound is determined according to relevant situation by the doctor, comprises the selection of patient's the state of an illness, compound used therefor and administrated method, and therefore above-mentioned dosage range can limit content of the present invention in no instance.
Following embodiment will illustrate that X of the present invention is R 1(HO)-formula I compound C=C(CN), beginning is to be prepared into based on the Z of Z and the mixture of E isomer.The purified Z isomer product that obtains.
Embodiment 1
(ⅰ) cyano propanone, sodium salt
Adopt mechanical stirring, make sodium piece (7.36 gram) be dissolved in dehydrated alcohol (368 milliliters), this is reflected under the nitrogen atmosphere and carries out.Stir the hot solution that generates, drop to about 20 ℃ until temperature.
In 12 minutes, splash into 5-methyl-isoxazole (26.56 gram), stirred the white hot suspension that generates 1 hour 12 minutes, cooling and stirring 1 hour 24 minutes in water-bath then.
Leach white solid, wash with 40-60 ℃ of sherwood oil (50 milliliters) in strainer, vacuum-drying in 46 ℃ baking oven obtains the cyano propanone sodium salt.
(ⅱ) 2-(4-trifluoromethyl) thiophene
In flask,, generate stiff white suspension along with vigorous stirring is added to 4-5 amido benzotrifluoride (25 gram) in water (62.5 milliliters) and the concentrated hydrochloric acid (35 milliliters).
At ethanol/CO 2Cooling suspension in the bath in 0-3 ℃ and 15 minutes, is added water (39 milliliters) solution of Sodium Nitrite (11.3 gram) by dropping funnel.
The thin cream-colored suspension that generates stirred 24 minutes at 1-3 ℃, then, in 1-3 ℃ and 3 minutes, add thiophene (128.6 milliliters, 136.35 grams), after 1 minute, then in 1.5-3 ℃ and 4 minutes, add water (156 milliliters) solution of sodium acetate (anhydrous) (62.33 gram).
0-5 ℃ of mechanical stirring reaction mixture 3.5 hours, then room temperature magnetic agitation 62.5 hours.
This reaction mixture is transferred to separating funnel, remove the water layer of bottom, and extract with ether (2 * 75 milliliters).
Ether extraction liquid and top burgundy organic layer merge, water (4 * 15 milliliters) washing, MgSO 4Dry, filter with water pump, the vapor bath evaporation obtains gluey brown solid.
This solid is dissolved in the dehydrated alcohol that boils (40 milliliters), and cooling is 46 minutes in ice bath, filters then.Brown solid in the strainer washs with ice-cold dehydrated alcohol (3 * 10 milliliters), and the cream-colored solid of generation spends the night with silica dehydrator in vacuum drier, obtains the 2-(4-trifluoromethyl) thiophene, fusing point: 114.5 ℃.
(ⅲ) 5-(4-trifluoromethyl) thiophene-2-carboxylic acid
In nitrogen atmosphere and instrument through oven dry, the 2-(4-trifluoromethyl in the ether that magnetic agitation is crossed with the 3A molecular sieve drying (267 milliliters)) thiophene (20.387 gram).
This solution cools off in ice bath, and in 4-8 ℃ and 22 minutes, adds the hexane solution (78.6 milliliters) of the butyllithium of 1.6M.
This mixture restir 44 minutes in ice bath then, along with manual stirring, with about 2 minutes, is added to powdery CO with it carefully 2The ethereal sludge material in (making about 267 milliliters of slurry cumulative volume).
Mixture kept 9 minutes, intermittently stirred simultaneously, then, along with manual stirring, the superfine heart adds entry (400 milliliters), then transfers to separating funnel in 3 minutes, remove the ether layer, and water (1 * 100 milliliter) washing, and main water layer washs with ether (1 * 100 milliliter).
The water that merges adds concentrated hydrochloric acid and is adjusted to pH1, is settled out cream-colored solid, more after filtration, and water in strainer (1 liter of cumulative volume) washing.Final washing lotion pH value is 5.
Product is used silica dehydrator in vacuum drier, obtain the 5-(4-trifluoromethyl) thiophene-2-carboxylic acid, fusing point: 227 ℃.
(ⅳ) 2-azidocarbonyl-5-(4-trifluoromethyl) thiophene
Above-mentioned acid (21.241 gram) in the instrument of nitrogen atmosphere and process oven dry in the dimethyl formamide (74 milliliters) of magnetic agitation usefulness 4A molecular sieve drying.
Add triethylamine (14.5 milliliters, 10.6 grams), continuously stirring at ambient temperature is till dissolving fully.
Mixture is at ethanol/CO 2Cool off in the bath, in 0-2 ℃ and 26 minutes, add anhydrous dimethyl formamide (10 milliliters) solution of hexichol phosphoryl trinitride (21.47 gram).
Replace cooling bath with oil bath, this brown solution 35 ℃ ± 20 ℃ heating 1.5 hours, was cooled off 66.5 hours in envrionment temperature then.
This brown solution is annotated in ice (about 500 milliliters), produce cream-colored solid precipitation, with ethyl acetate (1 * 250 milliliter, 2 * 100 milliliters) extraction, the extraction liquid of merging is successively used saturated sodium bicarbonate aqueous solution (4 * 25 milliliters) and water (4 * 25 milliliters) washing.This extraction liquid MgSO 4Drying is filtered and 43 ℃ of vacuum-evaporation, is obtained the beige solid, i.e. 2-azidocarbonyl-5-(4-trifluoromethyl) thiophene, fusing point: 97 ℃.
(V) 2-isocyanato--5-(4-trifluoromethyl) thiophene
Stir with 22.179 grams of the above-mentioned trinitride in the dry toluene (400 milliliters) of 4A molecular sieve drying at the nitrogen atmosphere lower magnetic force, then, make it to reflux, obtain limpid solution with heating jacket.
Backflow stirred reaction mixture 1 hour 12 minutes, the brown turbid solution that generates stirred in ice bath 3 hours, leach cream-colored solid then, in strainer,, in vacuum drier, carry out drying with silica gel successively with toluene (50 milliliters) and 40-60 ℃ of oil (20 milliliters) washing.
Merging filtrate and washings 73 ℃ of vacuum-evaporation, obtain shallow brown oil, solidify when cool to room temperature.In 40-60 ℃ sherwood oil (100 milliliters), stir again, filter, with 40-60 ℃ of sherwood oil (2 * 20 milliliters) washing, this solid carries out drying with silica gel in vacuum drier in strainer, obtain 2-isocyanato--5-(4-trifluoromethyl) thiophene, fusing point: 64 ℃.
(ⅵ) 2-cyano-3-hydroxy-n-(5-(4-trifluoromethyl)-thiophene-2-yl) but-2-enamides
In the instrument of nitrogen atmosphere and drying, magnetic agitation is the cyano propanone sodium salt (6.41 restrain) in the dry and distilled tetrahydrofuran (THF) (105 milliliters) with fresh sodium.Solution cools off in ice bath, and in 1-4 ℃ and 15 minutes, adds the turbid solution of above-mentioned isocyanic ester (16.45 gram) in anhydrous tetrahydro furan (66 milliliters) of porphyrize.
Remove cooling bath, the brown suspension stirring after 9 minutes, is heated to 50 ℃ with oil bath, stirred 2 hours 13 minutes at 52-53 ℃ then.This mixture kept 67 hours under room temperature and nitrogen atmosphere, more after filtration, leached cream-colored solid, in strainer, wash with a small amount of tetrahydrofuran (THF), then, 46 ℃ of vacuum-dryings in baking oven.
Merging filtrate and washings carry out vacuum-evaporation, obtain the brown solid foam-like material.This material (550 milliliters) in water stirs, and adds 2N NaOH(25 milliliter) make and reach pH12, wash with ether then.
Water is removed a small amount of insoluble solids after filtration, adds concentrated hydrochloric acid along with stirring, and is adjusted to pH1.
Leach sedimentary cream-colored solid, water in strainer (750 milliliters) washing, dry in 46 ℃ vacuum drying oven.
Product is dissolved in the ethyl acetate of boiling (300 milliliters), and heat filtering makes it clarification, stores 19 hours in envrionment temperature.
Leach the cream coloured crystal, dry in 46 ℃ vacuum drying oven, obtain 2-cyano-3-hydroxy-n-(5-(4-trifluoromethyl) thiophene-2-yl) but-2-enamides, fusing point: 245-246 ℃.
Embodiment 2
(ⅰ) 2-(4-(1,1-diformazan ethyl) phenyl) thiophene
Mark part is with 1-bromo-4-(1,1-dimethyl) ethylbenzene (100 gram) distill anhydrous tetrahydro furan (150 milliliters) solution be added to magnesium metal (11.67 gram) that magnetic agitation distill anhydrous tetrahydro furan (100 milliliters) suspension in.After adding the thermal initiation Grignard reaction, with 1-bromo-4-(1,1 diformazan ethyl) benzene adds to keep this solvent ebullient speed.After the adding, reaction mixture refluxed heating 2 hours, question response mixture cool to room temperature, be injected into ice-cold 2-bromo thiophene (76.51 gram) carefully and containing two chloro-two (1, the 3-diphenyl phosphine) propane nickel II (0.15 gram) distill anhydrous tetrahydro furan (250 milliliters) solution in (see G.R.VanHecke and W.D.Horrocks, Inorg.Chem., the 1966th page, 5,1968).Add 4-(1,1-diformazan ethyl) behind the phenyl-magnesium-bromide solution, remove ice bath, in 0.75 hour, be that the 0.1-0.2 gram adds two (1, the 3-diphenyl phosphine) propane nickel II of two chloro-(2.75 gram) again with every part, adopt ice bath to make reaction mixture be back to room temperature.After adding whole catalyzer, stir dark brown solution, and reflux 2 hours, left standstill then 16 hours.The magnesium bromide of decantation precipitation separation separates with tetrahydrofuran (THF) washing and decantation, in this magnesium bromide water-soluble (500 milliliters), extract with ethyl acetate (2 * 200 milliliters), merge with the solution of decantation, be diluted to 1500 milliliters, with sodium hydrogen carbonate solution washing, MgSO with ethyl acetate 4Dry, activated carbon treatment is also filtered (3 times), and solvent removed in vacuo obtains brown oil (86.57 gram).This oil distills under 80-120 ℃/0.65 mmhg with the claisen still head, then by being surrounded by the 2 centimetres of Vigreux columns of 20 cm x and the atmospheric condenser redistillation of velveteen.Collect the cut of boiling point 100-112 ℃/0.35 mmhg, obtain 2-(4-(1,1-diformazan ethyl) phenyl) thiophene.
(ⅱ) 2-carboxyl-5-(4-(1,1-diformazan ethyl) phenyl) thiophene
Along with mechanical stirring, with 2-(4-(1,1-diformazan ethyl) phenyl) thiophene (111.6) gram is dissolved in the ether (1145 milliliters) with the 3A molecular sieve drying.
With ethanol/CO 2Bath is cooled to 0 ℃ with this solution, splashes into the hexane solution (458 milliliters) of 1.55M n-Butyl Lithium then in 0-19 ℃ and 46 minutes.
Continuously stirring is 2 hours again, makes temperature rise to 0 ℃ gradually from-19 ℃ during this period.
By means of nitrogen pressure,, reaction mixture was conveyed in 15 minutes in ether (575 milliliters) slurries of churned mechanically titanium dioxide carbon granules (about 1730 grams, the size of grain is 2 * 1 centimetres) by Glass tubing.
This mixture stirring after 1 hour 14 minutes, is added entry (2.88 liters) carefully, then add 2N sodium hydroxide solution (567 milliliters).
Stir after 29 minutes, spend the night and separate each layer.
Remove the alkali lye layer of bottom, add concentrated hydrochloric acid and be adjusted to pH1.
Remove by filter the pale precipitation thing, and water (2 liters) washing.
After 62 ℃ of vacuum-drying, obtain title compound, fusing point: 242 ℃.
(ⅲ) 2-azidocarbonyl-5-(4-(1,1-diformazan ethyl) phenyl) thiophene
Along with mechanical stirring, 2-carboxyl-5-(4-(1,1-diformazan ethyl) phenyl) thiophene (115.26 gram) be added to triethylamine (44.8 gram) and in the dimethyl formamide (346 milliliters) of 4A molecular sieve drying.
The solution that generates cools off with ice bath, splashes into anhydrous dimethyl formamide (58 milliliters) solution of hexichol phosphoryl trinitride (121.82 gram) in 2.5-15 ℃ and 15 minutes.
During adding, isolate the cream-colored solid of agglomerate.
Behind the restir 5 minutes, replace ice bath, stirred this mixture 1 hour 40 minutes, then, be injected in trash ice (2 liters) and the water (1.5 liters) at 37 ± 2 ℃ by heating jacket.
By removing by filter cream-colored solid, mechanical stirring 10 minutes in 0.1N sodium hydroxide solution (800 milliliters) then.
The solid water that leaches (2 liters of cumulative volumes) washing then in room temperature, is used silica gel vacuum-drying, fusing point: 104 ℃.
(ⅳ) 2-(4-(1,1-diformazan ethyl) phenyl]-5-isocyanato-thiophene
2-azidocarbonyl-the 5-of magnetic agitation (4-(1,1-diformazan ethyl) phenyl) thiophene (123.32 gram) is with toluene (1 liter) the solution reflux of 4A molecular sieve drying 1 hour 19 minutes.
60 ℃ of vacuum-evaporation, the deep cream solid that obtains is in drying at room temperature, fusing point: 76 ℃.
(V) 2-cyano group-N-(5-(4-(1,1-diformazan ethyl) phenyl) thiophene-2-yl)-3-hydroxyl but-2-enamides
Cyano propanone sodium salt (40.98 gram) suspension in and distillatory tetrahydrofuran (THF) (200 milliliter) dry through fresh sodium carries out mechanical stirring, and cools off with ice bath.
In 3-5 ℃ and 40 minutes, splash into 2-(4-(1,1-diformazan ethyl) phenyl)-the little turbid solution of anhydrous tetrahydro furan (400 milliliters) of 5-isocyanato-thiophene (100 gram).
Restir mustard seed look suspension was removed ice bath after 20 minutes in ice bath, continued to stir 52 minutes in envrionment temperature, put into 55 ± 2 ℃ of heating jacket internal heating then 1.5 hours.
After the vacuum-evaporation, remaining cream color slurry stirred 30 minutes in 0.7N sodium hydroxide (975 milliliters).
The insoluble cream-colored solid of elimination, alkaline filtrate is adjusted to pH1 by adding concentrated hydrochloric acid, the sedimentary cream-colored pasty solid of elimination, water (about 3 liters) washing, partly dry with 60 ℃ of vacuum.
In 2 liters of dehydrated alcohols, reflux and stirred this solid 15 minutes, in ice bath, stirred 45 minutes then.After the filtration,, and, use middle the stirring 10 minutes of the ethyl acetate of boiling (2.25 liters) of gac (5 gram) again, further purify 60 ℃ of vacuum-dryings with ice-cold ethanol (400 milliliters) washing.The elimination gac, with hot ethyl acetate (300 milliliters) washing, filtrate and washings merge, and adopt vacuum-evaporation, make volume reduce 1.5 liters in strainer.
Leave standstill 1 hour in ice bath after, elimination light green crystal is with 40-60 ℃ of sherwood oil (100 milliliters) washing, 45 ℃ of vacuum-dryings.
Crystalline solid uses 1N sodium hydroxide (750 milliliters) and ether (750) milliliter to stir at last, purifies.The alkali lye layer of bottom is removed.And be filtered to clarification.Add concentrated hydrochloric acid and be adjusted to pH1.Leach the cream-colored precipitated solid of generation, water in strainer (2 liters) washing, and through 60 ℃ of vacuum-dryings, fusing point: 226-228 ℃.
With preparing following compounds with quadrat method:
2-cyano group-N-(5-(4-(1-cyano group-1-first and second bases) phenyl) thiophene-2-yl)-and 3-hydroxyl but-2-enamides, fusing point: 222-224 ℃.(by 2-carboxyl-5-(4-(1-cyano group-1-first and second bases) phenyl) thiophene makes).
2-cyano group-N-(5-(4-fluorophenyl) thiophene-2-yl)-and 3-hydroxyl but-2-enamides, fusing point: 232-234 ℃.
(by 2-carboxyl-5-(4-fluorophenyl) thiophene makes).
2-cyano group-N-(5-(4-chloro-phenyl-) thiophene-2-yl)-and 3-hydroxyl but-2-enamides, fusing point: 252-254 ℃.
(by 2-carboxyl-5-(4-chloro-phenyl-) thiophene makes).
2-cyano group-N-(5-(4-(1,1-dimethyl propyl) phenyl) thiophene-2-yl)-and 3-hydroxyl but-2-enamides, fusing point: 211-213 ℃.
(making) by 2-carboxyl-5-((4-1,1-dimethyl propyl) phenyl) thiophene.
2-cyano group-N-(5-phenyl thiophene-2-yl)-and 3-hydroxyl but-2-enamides, fusing point: 240-241 ℃.
(making) by 2-carboxyl-5-phenyl thiophene.
2-cyano group-N-(5-(4-aminomethyl phenyl) thiophene-2-yl)-and 3-hydroxyl but-2-enamides, fusing point: 245-247 ℃.
(by 2-carboxyl-5-(4-aminomethyl phenyl) thiophene makes).
2-cyano group-N-(4-(4-(1,1-diformazan ethyl) phenyl) thiophene-2-yl)-and 3-hydroxyl but-2-enamides, fusing point: 243-246 ℃.
(by 2-carboxyl-4-(4-(1,1-diformazan ethyl) phenyl) thiophene makes).
Embodiment 3
(ⅰ) ethoxy-methyl acetoacetate
Methyl aceto acetate (130.14 gram), triethyl orthoformate (148.2 gram) and acetic anhydride (204.18 gram) reflux 90 minutes, remove volatile byproduct with rotary evaporator, obtain garnet oil (about 400 milliliters), through 15 centimetres of Vigreux column underpressure distillation, obtain 128 gram clarified oils (boiling point: 100-110 ℃, 1 mmhg).This product is Z and E(1: the 1) mixture of ethoxy-methyl acetoacetate.
(ⅱ) 5-methyl-isoxazole-4-yl carboxylic acid ethyl ester
Oxammonium hydrochloride (52.6 gram) water-soluble (150 milliliters) also stirs, and adds water (100 milliliters) solution of ice-cold sodium hydroxide (30.28 gram) simultaneously.This solution adds dehydrated alcohol (600 milliliters), restir 15 minutes after stirring 15 minutes.Ethoxy-methyl acetoacetate (128 gram) is dissolved in dehydrated alcohol (100 milliliters), and is added in this hydroxylamine solution.Stir after 30 hours, in rotary evaporator, remove desolvate (bathing 45 ℃ of temperature).Clarifying oil at 50-54 ℃/0.5 mmhg, is collected the clarified oil product through 15 centimetres of Vigreux column underpressure distillation.
(ⅲ) 5-methyl-isoxazole-4-yl carboxylic acid
5-methyl-isoxazole-4-yl carboxylic acid ethyl ester (65 gram) is at the 10MHCl(500 milliliter) in reflux 3 hours, crystallisation by cooling goes out product, after filtration and dry, obtains 42 and restrains white crystalline solid, fusing point: 134-136 ℃.
(ⅳ) 5-methyl-isoxazole-4-base carbonyl chloride
Thionyl chloride (118 gram) is added in 5-methyl-isoxazole-4-yl carboxylic acid (42 gram), stirs and adds dimethyl formamide (0.2 milliliter) in room temperature.Stirring and refluxing heated this solution 2 hours, removed remaining thionyl chloride in 50 ℃ of vacuum, used 15 centimetres of Vigreux column underpressure distillation residuums then, obtained oil, boiling point: 32-34 ℃/0.1 mmhg.
(V) 2-amino-4-(4-(1,1-diformazan ethyl) phenyl) thiazole
145.5 ℃ of the fusing points of this compound, according to Eilingsfeld, H, Neumann, P.; Seybold, G., Lenke D, and Friedrich, L., 44, No. 442 method therefors of european patent application are prepared.
(ⅵ) N-(4-(4-(1,1-diformazan ethyl) phenyl) thiazol-2-yl)-5-methyl-isoxazole-4-yl-carboxamides
2-amino-4-(4-(1,1-diformazan ethyl) phenyl)-thiazole (8 gram) and in methylene dichloride (20 milliliter) solution of mixture in the 3A molecular sieve drying of the pyridine (2.72 gram) of 3A molecular sieve drying with magnetic agitation, cool off with ice bath.This is reflected in the nitrogen atmosphere and carries out in the instrument of oven dry.
In 3.5-9 ℃ and 32 minutes, splash into anhydrous methylene chloride (50 milliliters) solution of 5-methyl-isoxazole-4-base carbonyl chloride (5 gram).
Remove ice bath, continue to stir 21.25 hours in envrionment temperature.
Reaction mixture is successively used 0.5N hydrochloric acid (2 * 20 milliliters) and water (2 * 20 milliliters) washing.Use MgSO 4Dry, filter and 55 ℃ vacuum-evaporation after, obtain remaining cream-colored solid, fusing point is 210 ℃.
Leach sedimentary white solid from the acid that merges and water washing liquor, water (2 * 100 milliliters) washing after 60 ℃ of vacuum-drying, obtains title compound, fusing point 219-220 ℃ (decomposition).
(ⅶ) 2-cyano group-N-(4-(4-(1,1-diformazan ethyl) phenyl) thiazol-2-yl)-3-hydroxyl but-2-enamides
N-(4-(4-(1,1-diformazan ethyl) phenyl) thiazol-2-yl)-5-methyl-isoxazole-4-yl-carboxamides (6.02 gram) joins in the solution of sodium hydroxide (0.496 gram) and water (20 milliliters), dimethyl sulfoxide (DMSO) (10 milliliters) and dehydrated alcohol (150 milliliters).
After 22 hours, add water (10 milliliters) solution of sodium hydroxide (0.496 gram) in stirring at room in addition, continue to stir after 24 hours,, obtain the oil of mustard seed look with 54 ℃ of these settled solutions of vacuum-evaporation.
This oil shakes mixed with 0.04N sodium hydroxide solution (2.5 liters) and ether (200 milliliters).
The filtering insoluble solids after ether (200 milliliters) washing, is suspended in 2N hydrochloric acid (75 milliliters), and is kept in the ultra sonic bath 5 minutes.
After filtration and water (6 * 50 milliliters) washing, with the cream-colored solids of 60 ℃ of vacuum-dryings, with the ethyl acetate of boiling (300 milliliters) recrystallize, obtain pure crotonamide, after 60 ℃ of vacuum-drying, this product fusing point is 226-228 ℃ (decomposition).
From prepare following compound with quadrat method:
2-cyano group-N-(5-phenyl thiazole-2-yl)-and 3-hydroxyl but-2-enamides, fusing point＞260 ℃.
Embodiment 4
(ⅰ) 4-(1,1-diformazan ethyl) acetophenone
Under room temperature and nitrogen atmosphere, in 1 hour with 4-(1,1-diformazan ethyl) benzene (50 gram) and Acetyl Chloride 98Min. (32.2 gram) be added drop-wise in churned mechanically methylene dichloride (100 milliliters, the anhydrous) suspension of aluminum chloride (52.2 restrain) together.That this mixture becomes is dark red/and brown, room temperature restir 3.5 hours, be poured on the ice (800 milliliters+400 milliliters), and add about 100 milliliters of dense HCl(), leave standstill, when ice is dissolved,, use MgSO then with ether (5 * 200 milliliters) extraction 4Drying, solvent removed in vacuo, vacuum distilling is purified, and obtains reddish oil, and boiling point is 70 ℃/0.25 mmhg.
(ⅱ) 1-(N, the N-dimethylamino)-3-(4-(1,1-diformazan ethyl) phenyl third-1-alkene-3-ketone
In 5 minutes, with N, dehydrated alcohol (2.5 milliliters) drips of solution of dinethylformamide diethyl acetal (5.01 gram) is added to 80 ℃ the 4-(1 of being heated to that is stirring, 1-diformazan ethyl) in dehydrated alcohol (50 milliliters) solution of acetophenone (5 gram), reflux is spent the night while stirring, with tlc monitoring reaction process, remaining ethanol is removed in decompression, the brown oil that obtains cools off in Cardice, obtains yellow solid, 40-60 ℃ of sherwood oil recrystallize of this product.
(ⅲ) the amino 4-(4-1 of 2-, 1-diformazan ethyl) phenyl) pyrimidine
Sodium Metal 99.5 (10.4 gram) is added in the dehydrated alcohol (40 milliliters), when sodium all dissolves, the alcohol sodium solution that so generates is added to Guanidinium carbonate (1.56 gram) and (1-(N, the N-dimethylamino)-3-(4-1,1-diformazan ethyl) phenyl) in dehydrated alcohol (40 milliliters) solution of third-1-alkene-3-ketone (2.5 gram) mixture, along with stirring, this mixture reflux spends the night.With tlc monitoring reaction process, the solids that cooling generates after filtration and wash with water, is removed Na 2CO 3, obtaining white crystalline solid, fusing point is 186 ℃.
(ⅳ) 2-cyano group-N-(4-(4-(1,1-diformazan ethyl) phenyl) pyrimidine-2-base)-3-hydroxyl but-2-enamides
Through embodiment 3 described method preparations, this product fusing point is 224-225 ℃ to described compound by step (ⅲ) intermediate.
Embodiment 5
(ⅰ) 2-(4-(1,1-diformazan ethyl) phenyl-1-methylpyrrole
Nitrogen atmosphere and-70 ℃, in 15 minutes, (79.65 milliliters of the hexane liquid that will contain butyllithium while stirring, 1.55M) splash in anhydrous tetrahydro furan (80 milliliters) solution of 1-methylpyrrole (10 gram), then, be warming up to room temperature (20 ℃) at this solution, after 1 hour, be added in anhydrous tetrahydro furan (160 milliliters) solution of Zinc Chloride Anhydrous (18.5 gram), (this zinc chloride before use, put into 300 ℃ of oven dryings 16 hours), the mixture that generates is in stirring at room after 1 hour, along with agitation and dropping to 1-bromo-4-(1,1-diformazan ethyl) anhydrous tetrahydro furan (200 milliliters) solution of benzene (17.52 gram), this anhydrous tetrahydro furan contains two (triphenyl phosphine) palladium II of chlorination (1.18 gram).Mixture when obtaining is in stirred overnight at room temperature, reflux 2 hours, be cooled to room temperature then, leave standstill hypsokinesis in 16 hours in room temperature and be injected into ethyl acetate (1000 milliliters), water (2 * 100 milliliters), 2M hydrochloric acid (2 * 100 milliliters) and saturated sodium bicarbonate solution (3 * 250 milliliters) wash.Ethyl acetate solution drying (MgSO 4), use solvent removed in vacuo, obtain in 135 ℃/0.1 mmhg distillatory raw product.
(ⅱ) 5-(4-(1,1-diformazan ethyl) phenyl-1-methylpyrrole-2-carboxylic acid
Nitrogen atmosphere and-75 ℃, in 1 hour, along with stirring butyllithium (in 24.84 milliliters of hexanes, 1.55M concentration) be added drop-wise to 2-(4-(1,1-diformazan ethyl) in anhydrous tetrahydro furan (150 milliliters) solution of phenyl-1-methylpyrrole (8 gram), after being warming up to room temperature and stirring 1 hour, this mixture is poured in the ether (400 milliliters) of carbonated solid piece (600 gram), carbonic acid gas is let alone evaporation.This ethereal solution is with 2M sodium hydroxide (3 * 100 milliliters) extraction, carries out acidifying and with ether (2 * 100 milliliters), ethyl acetate (2 * 100 milliliters) extraction water solution with 5M hydrochloric acid.Extraction liquid drying (MgSO 4), use solvent removed in vacuo, obtain 5-(4-(1,1-diformazan ethyl) phenyl-1-methylpyrrole-2-carboxylic acid, fusing point: 192～194 ℃.
(ⅲ) 2-cyano group-N-[5-(4-(1,1-diformazan ethyl) phenyl)-1-methylpyrrole-2-yl)-3-hydroxyl but-2-enamides
Described compound prepares through embodiment 2 described methods with above-mentioned intermediate.
Embodiment 6
(ⅰ) 5-bromine furans-2-carboxylate methyl ester
Boron trifluoride methanol (6.3 milliliters, 7.6 gram) is added in methyl alcohol (90 milliliters) solution of 5-bromine furans-2-carboxylic acid (10 gram) of stirring, and reflux is 5 hours under nitrogen atmosphere.Add boron trifluoride methanol (5 milliliters) again, this mixture reflux 5 hours is cooled to room temperature, leave standstill 10 hours after, solvent removed in vacuo, the sodium hydrogen carbonate solution (300 milliliters) that the residuum impouring is saturated, with ethyl acetate (3 * 200 milliliters) extraction.Extraction liquid is used MgSO with saturated sodium bicarbonate solution (2 * 100 milliliters) washing 4Drying, solvent removed in vacuo obtains 5-bromine furans-2-carboxylate methyl ester, and fusing point is 62 ℃.
(ⅱ) 1-(1, the 1-dimethyl ethyl)-4-tributyl stannyl benzene
While stirring with 1-bromo-4-(1,1-diformazan ethyl) anhydrous tetrahydro furan (40 milliliters) solution of benzene (10.656 gram) splashes in anhydrous tetrahydro furan (10 milliliters) liquid of MAGNESIUM METAL (1.264 gram).After adding thermal booster reaction, splash into 1-bromo-4-(1,1-diformazan ethyl to keep solvent ebullient speed) benzene.After the adding, this mixture reflux 1 hour is cooled to room temperature then, drips anhydrous tetrahydro furan (20 milliliters) liquid of three normal-butyl chlorination tin (14.12 milliliters).This mixture reflux 1 hour is poured in the frozen water (300 milliliters), with ether (2 * 100 milliliters) extraction, with sodium bicarbonate (50 milliliters) washing, uses MgSO 4Drying, solvent removed in vacuo, the yellow liquid that obtains is poured on the flash chromatography silica gel on the clinkering thing (25 gram).This product hexane wash, treat that vacuum is removed hexane after, obtain colourless liquid, can be directly used in next reaction.
(ⅲ) 5-(4-(1,1-diformazan ethyl) benzofurane-2-carboxylate methyl ester
5-bromine furans-2-carboxylate methyl ester (2 gram), 4-(1, the 1-dimethyl ethyl)-and 4-(tributyl stannyl) benzene and chlorination be two-(triphenyl phosphine) palladium II (0.377 gram) anhydrous tetrahydro furan (25 milliliters) solution, reflux is 8 hours under nitrogen atmosphere, be poured into after cooling in the ethyl acetate (100 milliliters), with sodium bicarbonate (3 * 100 milliliters) washing, MgSO 4Drying is used solvent removed in vacuo, obtains 5-(4-(1, the 1-dimethyl ethyl) benzofurane-2-carboxylate methyl ester.
(ⅳ) 5-(4-(1,1-diformazan ethyl) benzofurane-2-carboxylic acid
Water (17.75 milliliters) solution of sodium hydroxide (1.42 gram) is added to the 5-(4-(1 that vigorous stirring, 1-diformazan ethyl) in tetrahydrofuran (THF) (100 milliliters) solution of benzofurane-2-carboxylate methyl ester (4.579 gram), stirring at room 17 hours, solvent removed in vacuo, residuum is used the 2M hcl acidifying after being dissolved in 10% sodium hydrogen carbonate solution (200 milliliters).This mixture extracts with ether (3 * 200 milliliters), and this ethereal solution washes with water, MgSO 4Drying, solvent removed in vacuo obtains 5-(4-(1,1-diformazan ethyl) benzofurane-2-carboxylic acid, fusing point is 230 ℃.
(ⅴ) 2-cyano group-N-[5-(4-(1,1-diformazan ethyl) phenyl)-1-furans-2-yl)-3-hydroxyl but-2-enamides
Described compound prepares through embodiment 2 described methods with above-mentioned intermediate.
Embodiment 7
List following pharmaceutical preparation with way of example:
(ⅰ) injection formulations
The injection formulations that contains 5 mg/ml activeconstituentss is prepared by following compositions
250 milligrams of activeconstituentss
0.1M 10 milliliters in sodium hydroxide
2 milliliters of 1/10N hydrochloric acid
The isotonic saline solution that contains 5%Poloxamer F68 is assigned to 50 milliliters
(ⅱ) hard capsule preparaton
100 milligrams of activeconstituentss
50 milligrams of 1% polysiloxane starch
50 milligrams of fluidity starches
(ⅲ) tablet formulation agent
100 milligrams of activeconstituentss
185 milligrams of Microcrystalline Celluloses
3 milligrams of Xylo-Mucines (crosslinked)
10 milligrams of polyvinylpyrrolidones
1 milligram of Magnesium Stearate
Embodiment 8
Concanavalin A with the Rats Spleen cell responds as main in-vitro evaluation, to determine the activity of The compounds of this invention.Many methods of definite concanavalin A response have been narrated in the literature.The method that is adopted is similar to Lacombe P etc. at FEBS 3,048 191,227～230 pages of described methods.Only be without Hepes that with the difference of this method each is cultivated the cave and uses 2 * 10 5Individual cell adopts concanavalin A (3 mcg/ml).The demand (2 * 10 of 2 mercapto ethanol -5M), add 0.1 microcurie tritiate thymidine, after 4 hours, gather cell.
For example embodiment 2 described The compounds of this invention when 10 micro-molar concentration dosage, all are higher than 50% inhibition degree.

Claims (5)

1, a kind of method for preparing following general formula compound and its esters:
Figure 871055155_IMG2
In the formula: X is R 1(HO) C=C (CN)-, R 1(CO)-CH (CN)-,
R 1Be methyl, R 2Be hydrogen, R 3, R 4, R 5, R 6In, one hydrogen, halogen, C 1-C 6The low alkyl group that alkyl, halogen atom or cyano group replace, other three all is hydrogen,
Y is 2,5-thienyl, 2,5-furyl, 2,5-thiazolyl, 2,6-pyrimidyl, 3,5-isothiazolyl, 2,5-pyrryl, 2,6-pyridyl, 2,5-oxazolyl, 2,5-imidazolyl, 2,4-thienyl;
This method comprises:
(a) formula IV compound and formula (V) compound reaction,
In the formula: M is an alkali valence metal ion, R 1And R 3To R 6Definition the same, can be arbitrarily and acid-respons with the salt that generates thus, obtaining wherein, X is R 1(HO) C=C (CN)-free hydroxy compound,
(b) amine of formula (VII) compound and formula (VIII) reaction,
Figure 871055155_IMG4
In the formula: Z is a halogen, chlorine preferably, R 1To R 6Definition the same,
X is in the compound that obtains
Figure 871055155_IMG5
(c) formula VI compound and alkali reaction,
Figure 871055155_IMG6
In the formula: R 1To R 6Definition the same, can be arbitrarily and acid-respons with the salt that generates thus, obtaining wherein, X is R 1(HO) C=C (CN)-free hydroxy compound,
Or
(d) hydrolyzing type (IX) compound,
Figure 871055155_IMG7
(Ⅸ)
In the formula, R 1To R 6Definition the same, R 10It is leavings group.
2, according to claim 1, preparing wherein, X is
Figure 871055155_IMG8
The method of compound.
3, according to claim 1 or 2, prepare wherein that Y is 2,5-thienyl or 2, the method for the compound of 4-thienyl.
4, according to claim 1 or 2, prepare wherein R 6Be hydrogen, C 1-4The C that alkyl, halogen replace 1-4Alkyl or carbonatoms be no more than 6-CR 7R 8R 9, R wherein 7, R 8And R 9Respectively be C 1-3The method of the compound of alkyl.
5, according to claim 1, prepare the method for following formula: compound and its esters:
Figure 871055155_IMG9
In the formula: R 1Be methyl, R 2Be hydrogen, R 7, R 8And R 9Respectively be C 1-3Alkyl, R 7, R 8, R 9Total carbon atom number is no more than 5, and the definition of Y is the same.
CN87105515A 1986-08-08 1987-08-07 Preparing method for butyrumid derivative Expired - Fee Related CN1021050C (en)

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